Mechanisms of action of the antidepressants fluoxetine and the substance P antagonist L-000760735 are associated with altered neurofilaments and synaptic remodeling

Antidepressants are widely prescribed in the treatment of depression, although the mechanism of how they exert their therapeutic effects is poorly understood. To shed further light on their mode of action, we have attempted to identify a common proteomic signature in guinea pig brains after chronic treatment with two different antidepressants. Both fluoxetine and the substance P receptor (NK1R) antagonist (SPA) L-000760735 altered cortical expression of multiple heat shock protein 60 forms along with neurofilaments and related proteins that are critical determinants of synaptic structure and function. Analysis of NK1R -/- mice showed similar alterations of neurofilaments confirming the specificity of the effects observed with chronic NK1R antagonist treatment. To determine if these changes were associated with structural modification of synapses, we carried out electron microscopic analysis of cerebral cortices from fluoxetine-treated guinea pigs. This showed an increase in the percentage of synapses with split postsynaptic densities (PSDs), a phenomenon that is characteristic of activity-dependent synaptic rearrangement. These findings suggest that cortical alterations of the neurofilament pathway and increased synaptic remodeling are associated with the mechanism of these two antidepressant drug treatments and may contribute to their psychotherapeutic actions. (C) 2004 Elsevier BY All rights reserved.